Effects of Aerobic Exercise on Skeletal Muscle Remodeling in Colon Cancer

PROJECT SUMMARY/ABSTRACT
Postdiagnosis physical activity is associated with a lower risk of cancer recurrence and death in colon cancer
survivors. However, the biological mechanisms that underpin the effects of physical activity on cancer
recurrence and death are poorly understood. Skeletal muscle is the most abundant tissue in the human body,
representing 40% of body weight and 30% of basal energy expenditure. Skeletal muscle fat infiltration, known
as myosteatosis, is an ectopic triglyceride depot that causes insulin resistance and inflammation. One in three
colon cancer survivors has myosteatosis. Myosteatosis increases the risk of cancer recurrence, cardiovascular
disease, and death in colon cancer survivors. Among older adults, myosteatosis predicts poor muscle strength
and subsequent disability, which is relevant because 62% of colon cancer survivors have functional limitations,
and these limitations erode quality of life and compromise longevity. We hypothesize that structured exercise
training remodels skeletal muscle composition (Aim 1), corrects muscle metabolic inflexibility (Aim 2), and
increases muscle function (Aim 3) in a manner consistent with an improved cancer prognosis and reduced risk
of competing morbidity and mortality. In response to PAR-18-893 "Physical Activity and Weight Control
Interventions Among Cancer Survivors: Effects on Biomarkers of Prognosis and Survival," we will conduct a
randomized controlled trial of structured aerobic exercise training in 138 stage I-III colon cancer survivors.
Subjects will be recruited using the Louisiana Tumor Registry, a population-based registry funded by the NCI’s
Surveillance, Epidemiology and End Results (SEER) Program to reflect the socioeconomic diversity of the
region. Subjects will be randomized to stretching attention control or 225 min/wk of moderate-intensity aerobic
exercise (70% heart rate reserve) for 12-weeks. Aim 1 will test the hypothesis that aerobic exercise decreases
whole-body intermuscular adipose tissue measured using whole-body magnetic resonance imaging. Aim 2 will
test the hypothesis that aerobic exercise decreases postprandial triglyceride concentration and increases free
fatty acid oxidation measured using an isotopically labeled liquid mixed meal containing [U-13C]palmitate. Aim
3 will test the hypothesis that aerobic exercise increases lower extremity skeletal muscle strength and physical
function using Biodex dynamometry and 10-step stair climb power. Myosteatosis is common and compromises
the health of colon cancer survivors. Identifying the health-promoting mechanisms of physical activity would
facilitate precision exercise prescriptions that are patient-centered and proven to have a high probability of
clinical benefit. The proposed aims will leverage a transdisciplinary team's synergies to offer comprehensive
and definitive insight into a novel biological mechanism of physical activity and cancer prognosis at the junction
of muscle physiology and adipocyte biology.

Grant Number: 7R01CA270274-04
NIH Institute/Center: NIH
Principal Investigator: Justin Brown